Axon-glial interactions are critical for the induction of myelination and the domain organization of myelinated fibers. We recently reported that in the peripheral nervous system (PNS) neurons and myelinating Schwann cells express a new set of cell adhesion molecules called the Nectin-like (Necl) proteins. In particular, Necl-1 on axons mediates adhesion by specifically binding to Necl-4 on Schwann cells. We showed that Necl-4 is required to initiate PNS myelination. These results implicate the Necl proteins as new, crucial mediators of axon-glia interactions. A key question is how the Necl proteins, and in particular Necl-4, mediates Schwann cell myelination. The Necls mediate cell adhesion though their Ig-like extracellular domain, and interact with scaffolding intracellular proteins through a FERM- and PDZ-binding domains. Through these latter interactions the Necl proteins can assemble polarity and signaling complexes. In preliminary studies we have obtained evidence that Necl-4 interacts with the polarity protein Par-3. These studies have also pointed out a possible interaction (direct or indirect) between Necl-4 and the Schwann cell ErbB receptors that transduce the instructive, axon-derived myelinating signal. Using mutant versions of Necl-4 in combination with lentiviral knockdown/rescue strategies, in vivo an in vitro, we will characterize the requirement of the PDZ-binding domain of Necl-4 in the initial stages of Schwann cell myelination, address the functional significance of the Necl-4/Par-3 interaction, and investigate how Necl-4 influence ErbB receptor signaling. The overall goal of this project is to provide novel insights into the mechanisms that regulate myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies.